Endothelin antagonist and beta receptor blocking agent as combined preparations

ABSTRACT

A combination of endothelin antagonists and beta-receptor blockers is described. The combination is suitable for controlling diseases.

The present invention relates to novel pharmaceutical combinationpreparations which are suitable for treating disorders based onvasoconstriction and which comprise a beta-receptor blocker and anendothelin antagonist.

Combination preparations which are suitable for treating disorders basedon vasoconstriction and which comprise a beta-receptor blocker and anendothelin antagonist have already been disclosed (WO 92/13545).However, the activity of these active compound combinations isunsatisfactory.

Combinations having improved properties have now been found.

The present invention provides a combination of an endothelin antagonistof the formula I

in which the substituents are as defined below:

R¹ is C₁-C₄-alkyl, C₁-C₄-alkoxy;

R² is C₁-C₄-alkyl, C₁-C₄-alkoxy;

R³ is C₁-C₈-alkyl, which may be substituted by a phenyl radical whichfor its part may be substituted by one or two C₁-₄-alko-xy radicals,

z is oxygen or a single bond,

and a beta-receptor blocker. Preferred endothelin antagonists are thosecompounds of the formula I where the substituents are as defined below:

R¹: C₁-C₂-alkyl, C₁-C₂-alkoxy

R²: C₁-C₂-alkyl, C₁-C₂-alkoxy

R³ is C₁-C₂-alkyl which may be substituted by a phenyl radical whch forits part may be substituted by one or two C₁-2-alkoxy radicals,

Z is oxygen or a single bond.

Particularly suitable endothelin antagonists are the compounds:

Suitable beta-receptor blockers are, in particular, acebutolol,alprenolol, atenolol, metoprolol, bupranolol, penbutolol, propranolol,esmolol, bisoprolol, carazolol, talinolol, mepindolol, sotalol,metipranolol, pindolol, carteolol, tetratolol, celiprolol, nadolol,oxprenolol and bopindolol. In particular, carvedilol and bucindolol maybe mentioned.

The combination of a β-blocker with an inhibitor of the ET-system can beused as a composition for treating diseases which are based onvasoconstriction or associated with pathological vasoconstriction.Examples are: all forms of high blood pressure (including pulmonaryhypertension), coronary heart diseases, cardiac insufficiency, renal andmyocardiac ischemia, acute and chronic renal insufficiency.

Diseases which are associated with vasoconstriction or other biologicaleffects of endothelin and/or angiotensin II are, in particular, thecontrol and/or prevention of coronary disorders, cardiovasculardisorders, such as hypertension, cardiac insufficiency, ischemia (inheart, brain, gastrointestinal tract, liver and/or kidney) orvasospasms. Other examples of diseases which can be treated are renaland myocardiac ischemia, renal insuffiency, dialysis, subarachnoidalhaemorrhage, Raynaud's syndrome, portal high pressure and pulmonary highpressure and also the treatment of gastric and duodenal ulcers and ofstasis ulcer where vasoconstriction is involved. Finally, in asthmapatients the concentration of endothelin in the bronchial discharge isincreased. In migraine attacks, too, increased endothelin levels in theblood plasma are observed. The combination can therefore also be used inthese cases.

When the combination according to the invention is administered, thereis a significant increase of the antihypertensive properties and theduration of action compared with the individual substances, and thiseffect is superadditive. Accordingly, the doses of the individual activecompounds can be reduced considerably. Thus, there is a lower risk ofadverse effects during administration.

The weight ratio of β-receptor blocker to endothelin antagonists isusually in the range from 50:1 to 1:500, preferably from 10:1 to 1:100and in particular from 2:1 to 1:50.

The combinations according to the invention are generally administeredorally, for example in the form of uncoated, lacquered or sugar-coatedtablets, hard and soft gelatin capsules, solutions, emulsions orsuspensions. However, administration can also take place rectally, forexample in the form of suppositories, or parenterally, for example inthe form of solutions for injection. Administration of the activecompound can take place in the form of products which contain bothactive compounds together, such as tablets or capsules, or separately asad hoc combination of single substances, which can be administeredconcurrently or sequentially.

To produce uncoated, lacquered or sugar-coated tablets and hard gelatincapsules, a combination according to the invention can be processed withpharmaceutically inert inorganic or organic excipients. Excipients ofthese types which can be used for uncoated and sugar-coated tablets andhard gelatin capsules are lactose, corn starch or derivatives thereof,talc, stearic acid or salts thereof. Suitable excipients for softgelatin capsules are vegetable oils, waxes, fats, semisolid and liquidpolyols.

Suitable excipients for producing solutions and syrups are, for example,water, polyols, sucrose, invert sugar, glucose and the like. Suitableexcipients for solutions for injection are water, alcohols, polyols,glycerol, vegetable oils. Suitable excipients for suppositories arenatural or hydrogenated oils, waxes, fats, semiliquid or liquid polyolsand the like.

The pharmaceutical preparations may additionally comprise preservatives,solubilizers, stabilizers. Wetting agents, emulsifiers, sweeteners,colorants, flavorings. Salts to alter the osmotic pressure, buffers,coating agents and/or antioxidants.

The unexpected advantageous properties of the combinations according tothe invention are demonstrated by the tests below:

In a crossover design, the test substance was administered orally as acapsule to chronically instrumented male beagle dogs (approx 14 kg). Thecapsule either contained nothing (control N=5), compound A (10 mg/kg,N=10), bucindolol (0.1 mg/kg; N=5) or the combination bucindolol +compound A (0.1+10 mg/kg; N=5). In between the individualadministrations, a washing phase of at least one week was observed. Thesystolic and the diastolic blood pressure were measured using a StathamTransducer P 23 Db, from which the mean arterial blood pressure wascalculated. The blood pressure was recorded for 6 h (MI², ModularInstrumente, USA).

Table 1 shows that the blood pressure in the control group and in thegroup treated with bucindolol does not decrease. With compound A, aslight reduction in blood pressure can be observed. The combination ofbucindolol with the ET antagonist compound A (0.1+10 mg/kg) resulted ina considerable lowering of the blood pressure.

Table 1:

Development of the mean arterial blood pressure (mmHg, change withrespect to the initial value) in normotensive awake dogs after oraladministration of different substances, what is shown are the meanvalues

Initial N value 1h 2h 3h 4h 5h 6h Placebo 10 103 3 2 2 1 1 1 Compound A10 99.6 −5.9 −8.9 −9.0 −9.1 −8.4 −8.2 10 mg/kg Bucindolol 5 100.4 −0.8−3.8 −3.4 −3.8 −3.8 −1.4 0.1 mg/kg Combination 5 100.8 −8.8 −15.2 −17−15.6 −13.4 −11.8 A + Bu 10 + 0.1 mg/kg

The following examples illustrate the invention.

EXAMPLE 1

Lacquered tablets of the following composition were prepared:

Compound A 100.0 mg Bucindolol 10.0 mg Anhydrous lactose 30.0 mgMicrocrystalline cellulose 30.0 mg Polyvinylpyrrolidone 20.0 mgMagnesium stearate 5.0 mg Polyethylene glycol 6000 0.8 mg Iron oxideyellow 1.2 mg Titanium dioxide 0.3 mg Talc 0.7 mg

Compound A, bucindolol, the lactose, the gellulose and thepolyvinylpyrrolidone are wet-granulated and dried. The screened granulesare mixed with the magnesium stearate, and the ready-to-be-compressedmixture is compressed to oval tablet cores each weighing 190.0 mg. Thecores are then lacquer-coated until the lacquer-coated tablets havereached a final weight of 200 mg.

EXAMPLE 2

Preparation of hard gelatin capsules of the following composition:

Compound A 100.0 mg Bucindolol 30.0 mg Cryst. lactose 18.0 mgPolyvinylpyrrolidone 15.0 mg Microcrystalline cellulose 17.5 mg Sodiumcarboxymethyl starch 10.0 mg Talc 9.0 mg Magnesium stearate 3.0 mg

The first five components are wet-granulated and dried. The granules aremixed with the sodium carboxymethyl starch, the talc and the magnesiumstearate, and the mixture is packed into size 1 hard gelatin capsules.

We claim:
 1. A combination of an endothelin antagonist of the formula I

in which the substituents are as defined below: R¹ is C₁-C₄-alkyl,C₁-C₄-alkoxy; R² is C₁-C₄-alkyl, C₁-C₄-alkoxy; R³ is C₁-C₈-alkyl whichmay be substituted by a phenyl radical which for its part may besubstituted by one or two C₁₋₄-alkoxy radicals, Z is oxygen or a singlebond, and a beta-receptor blocker.
 2. A pharmaceutical preparation,comprising a combination as claimed in claim
 1. 3. A process forpreparing a pharmaceutical preparation, which comprises bringing amixture of a beta-receptor blocker and an endothelin antagonist asclaimed in claim 1 into a pharmaceutical administration form.
 4. Apharmaceutical preparation comprising a beta-receptor blocker and anendothelin antagonist as claimed in claim 1, for simultaneous, separateor successive use in the treatment of diseases.